IGFBP5, a member of the IGF (insulin-like growth factor) binding protein family, is known to play an important role in various cellular functions including cell proliferation. IGFBP5 translocates to the cell nucleus due to its NLS (nuclear localization signal) and is also secreted outside the cell, but the intranuclear and extracellular functions of IGFBP5 have not yet been well studied. Recently, IGFBP5 has been reported to have transactivation activity. IGFBP5 may be largely divided into three domains (N-terminus, L-domain, and C-terminus), with the presence of an IGF binding site in the N-terminal domain, an NLS in the C-terminal domain, and a heparin binding site in both the L-domain and the C-terminal domain. Both the glycosylation and the phosphorylation of IGFBP5 are known to inhibit the heparin binding of IGFBP5, but the biological significance of the glycosylation and the phosphorylation is not well understood.
IGFBP5 modulates the functions of IGF-I and IGF-II by inhibiting the binding of IGF-I or IGF-II to their receptors while IGF-independent functions of IGFBP5 are also reported. The functions of IGFBP5 have been studied transgenic and knockout mice of IGFBP5. Increased IGFBP5 production in transgenic mice resulted in high neonatal mortality, growth inhibition and delayed muscle development. In female transgenic mice, IGFBP5 was also found to induce reduced fertility, and premature cell death in the mammary glands. IGFBP5 knockout mice demonstrated delayed mammary gland involution, reflecting the involvement of IGFBP5 in apoptosis.
TNF-α (tumor necrosis factor-alpha) is known as a pro-inflammatory cytokine which often promotes inflammatory responses and causes other diseases (e.g., septic shock due to exposure of endotoxin). TNF-α is released from macrophages, monocytes and natural killer cells and play an important role in inflammatory and immune responses. TNF-α shows the following various in vitro or in vivo effects: (i) vascular thrombosis and tumor necrosis; (ii) inflammation; (iii) activation of macrophages and neutrophils; (iv) leukocytosis; (v) apoptosis; and (vi) shock. In addition, TNF-α is associated with a variety of cancers, arthritis, psoriasis, endotoxic shock, sepsis, autoimmune diseases, infections, obesity, and cachexia.